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Abstract
The progression of cancer is associated with increases in amino acid uptake by cancer cells. Upon their entry into cells through specific transporters, exogenous amino acids are used to synthesize proteins, nucleic acids and lipids and to generate ATP. The essential amino acid leucine is also important for maintaining cancer-associated signaling pathways. By upregulating amino acid transporters, cancer cells gain greater access to exogenous amino acids to support chronic proliferation, maintain metabolic pathways, and to enhance certain signal transduction pathways. Suppressing cancer growth by targeting amino acid transporters will require an in-depth understanding of how cancer cells acquire amino acids, in particular, the transporters involved and which cancer pathways are most sensitive to amino acid deprivation. L-Type Amino Acid Transporter 1 (LAT1) mediates the uptake of essential amino acids and its expression is upregulated during the progression of several cancers. We will review the upstream regulators of LAT1 and the downstream effects caused by the overexpression of LAT1 in cancer cells.
Highlights
System L TransportersThe synthesis of biomass prior to cell proliferation is heavily dependent on the acquisition of exogenous amino acids that, upon being transported into cells, are used to synthesize proteins, nucleic acids, lipids, and ATP [1]
We have recently reported that L-Type Amino Acid Transporter 1 (LAT1) is an aryl hydrocarbon receptor (AHR) target gene and that reducing AHR or LAT1 with short interfering RNA reduces the proliferation of MCF7 and MDA-MB-231 breast cancer cells [9]
In addition to being responsive to exogenous ligands, the AHR has a constitutive activity that modulates gene expression in breast cancer [27]. In this regard, silencing AHR in MCF7 and MDA-MB-231 cells decreased the LAT1 mRNA and LAT1 protein, indicating that constitutive AHR activity promotes the transcription of LAT1 in these breast cancer models [9]. These results suggest that the regulation of LAT1 by AHR in breast cancer could be important for the progression of this disease
Summary
The synthesis of biomass prior to cell proliferation is heavily dependent on the acquisition of exogenous amino acids that, upon being transported into cells, are used to synthesize proteins, nucleic acids, lipids, and ATP [1]. LAT1 supports mTORC1 activity, it reinforces MYC and EZH2 signaling in cancer cells We will review these LAT1-supported downstream effects. Maintaining a high expression and activity of LAT1 in cancer requires a large supporting cast of proteins consisting of a chaperone protein, glutamine transporters, and upstream regulators of LAT1 expression. LAT1 silencing led to smaller tumors in mice, reductions in leucine uptake, reductions in mTORC1 activity, amino acid stress, decreases in proliferation. LAT1 silencing led to reductions in MYC translation, decreases in leucine uptake, smaller tumors in mice, decreases in proliferation, altered cancer cell metabolism, many gene expression changes. LAT1 silencing led to smaller tumors in mice, decreases in metastasis in mice, reductions in leucine uptake, reductions in mTORC1 activity, amino acid stress, decreases in proliferation, increases in apoptosis, many gene expression changes
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